# Molecular Mechanisms and Treatment of Diffuse Axonal Injury

> **NIH NIH K08** · UNIVERSITY OF PENNSYLVANIA · 2020 · $150,215

## Abstract

Project Summary
 This new investigator proposal describes a five-year training program for the development of a physician-
scientist career studying traumatic brain injury (TBI). This investigator completed a Ph.D. in neurobiology
focused on mechanisms and neuroinflammatory responses to diffuse axonal injury (DAI). This investigator
completed neurosurgery residency, two fellowships in pediatric neurosurgery and pediatric spinal deformity,
and is currently a Clinical Instructor at the University of Pennsylvania. In carrying out the proposed research,
the principle investigator will acquire expertise in protein biochemistry, knockout genomics, behavioral studies,
and advanced neuroimaging techniques. Dr. Douglas Smith, Professor and Chair of Research in the
Department of Neurosurgery, will mentor the principle investigator's scientific development. An advisory
committee of outstanding, nationally recognized scientists will provide scientific and career advice. The
Department of Neurosurgery at the University of Pennsylvania is committed to providing an ideal setting and
resources to ensure the principle investigator's success. The research proposal and environment will allow the
principle investigator to develop an academic career and become a leader in the neurotrauma community.
 Research will focus on the selective vulnerability of unmyelinated axon segments to initiating mechanisms
of diffuse TBI as well as treatment strategies to overcome DAI pathobiology. DAI pathogenesis proceeds
through a cascade of events leading to delayed or secondary axotomy. This creates a therapeutic window
during which treatments may mitigate or prevent axon disconnection. Mechanisms of DAI cytoskeletal injury
remain poorly understood and there are no treatments. The proposal seeks to determine precise DAI initiating
loci, explain the cytoskeletal protein spectrin's role in axonal injury, and investigate two neuroprotective
paradigms to mitigate DAI pathobiology. Using an experimental diffuse TBI murine model, the Specific Aims
include: 1.) Determine if the axon initial segment and/or nodes of Ranvier are sites of secondary axotomy
following diffuse TBI and 2.) Determine spectrin-mediated contributions to secondary axotomy following diffuse
TBI. This proposal will be the first to test the hypothesis that disruption of the spectrin cytosketeton at excitable
domains along the axon serves as a nidus for injury. Neuroprotective paradigms include preservation of the
spectrin cytoskeleton through exogenous and endogenous inhibition of the protease calpain, which targets
spectrin for degradation. The proposed research will improve our understanding of DAI-mediated cytoskeletal
injury and test neuroprotective strategies designed to prevent secondary axotomy. The integration of histology,
behavioral outcomes, and advanced neuroimaging techniques will create a model that predicts injury severity
and prognosticates recovery after diffuse brain injury.

## Key facts

- **NIH application ID:** 10023949
- **Project number:** 5K08NS110929-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Brian J. Kelley
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $150,215
- **Award type:** 5
- **Project period:** 2019-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023949

## Citation

> US National Institutes of Health, RePORTER application 10023949, Molecular Mechanisms and Treatment of Diffuse Axonal Injury (5K08NS110929-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10023949. Licensed CC0.

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